2. Academic Validation
  3. The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator

The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator

  • Eur J Pharmacol. 2014 Feb 5:724:102-11. doi: 10.1016/j.ejphar.2013.12.031.
Philip E Brandish 1,  Kenneth Anderson 2,  Gretchen A Baltus 3,  Chang Bai 2,  Christopher J Bungard 2,  Patricia Bunting 2,  Alan Byford 3,  Chi-Sung Chiu 3,  Milenko Cicmil 3,  Halea Corcoran 2,  Danielle Euler 2,  John E Fisher 2,  Carlo Gambone 2,  Martha Hasbun-Manning 2,  Nelly Kuklin 3,  Elizabeth Landis 2,  Traci Q Lifsted 2,  Sheila McElwee-Witmer 2,  Ian S McIntosh 2,  Robert S Meissner 2,  John Miao 3,  Helen J Mitchell 2,  Amy Musselman 2,  Azriel Schmidt 2,  John Shin 3,  Peter Szczerba 2,  Charles D Thompson 2,  Catherine Tribouley 3,  Robert L Vogel 2,  Sudha Warrier 2,  James C Hershey 2
Affiliations

Affiliations

  • 1 Merck & Co., Inc., Boston, MA 02115, United States. Electronic address: philip.brandish@merck.com.
  • 2 Merck & Co., Inc., West Point, PA 19422, United States.
  • 3 Merck & Co., Inc., Boston, MA 02115, United States.
PMID: 24374007 DOI: 10.1016/j.ejphar.2013.12.031
Abstract

Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the Glucocorticoid Receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective Glucocorticoid Receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting Insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, Animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.

Keywords

Diabetes; Glucocorticoid; Glucocorticoid receptor; Glucose; MK-5932.

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